scholarly journals Impact of Pre and Post Variant Filtration Strategies on Imputation

2020 ◽  
Author(s):  
Celine Charon ◽  
Rodrigue Allodji ◽  
Vincent Meyer ◽  
Jean-François Deleuze
Keyword(s):  
Quality Control ◽  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Direct Effects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Conservative Post

Abstract Quality control methods for genome-wide association studies and fine mapping are commonly used for imputation, however, they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1,031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1,089 NCBI recorded individuals for additional validation.Without variant pre-filtration based on quality control (QC), we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) <0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). As a result, to maintain confidence and enough SNVs, we propose here a 2-step post-filtration approach to increase the number of very rare and rare variants compared to conservative post-filtration methods.

scholarly journals Impact of pre- and post-variant filtration strategies on imputation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Céline Charon ◽  
Rodrigue Allodji ◽  
Vincent Meyer ◽  
Jean-François Deleuze
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Quality Score ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Direct Effects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Filtering Procedure

AbstractQuality control (QC) methods for genome-wide association studies and fine mapping are commonly used for imputation, however they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1089 NCBI recorded individuals for additional validation. Without QC-based variant pre-filtration, we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E−04–1E−03) and rare variants (1E−03–5E−03) (p < 1E−04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) < 0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E−04). Thus, to maintain confidence and enough SNVs, we propose here a two-step filtering procedure which allows less stringent filtering prior to imputation and post-imputation in order to increase the number of very rare and rare variants compared to conservative filtration methods.

scholarly journals Reproducibility in the UK biobank of genome-wide significant signals discovered in earlier genome-wide association studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jack W. O’Sullivan ◽  
John P. A. Ioannidis
Keyword(s):  
Effect Size ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
The Uk

AbstractWith the establishment of large biobanks, discovery of single nucleotide variants (SNVs, also known as single nucleotide polymorphisms (SNVs)) associated with various phenotypes has accelerated. An open question is whether genome-wide significant SNVs identified in earlier genome-wide association studies (GWAS) are replicated in later GWAS conducted in biobanks. To address this, we examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, “replication” GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNVs (of which 6289 reached P < 5e−8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0%; although lower for binary than quantitative phenotypes (58.1% versus 94.8% respectively). There was a 18.0% decrease in SNV effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNV effect size, phenotype trait (binary or quantitative), and discovery P value, we built and validated a model that predicted SNV replication with area under the Receiver Operator Curve = 0.90. While non-replication may reflect lack of power rather than genuine false-positives, these results provide insights about which discovered associations are likely to be replicated across subsequent GWAS.

scholarly journals Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

2016 ◽  
Vol 283 (1835) ◽  
pp. 20160569 ◽  
Author(s):  
M. E. Goddard ◽  
K. E. Kemper ◽  
I. M. MacLeod ◽  
A. J. Chamberlain ◽  
B. J. Hayes
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Quantitative Traits ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Crop Breeding ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

scholarly journals Genome-Wide Association Studies for the Concentration of Albumin in Colostrum and Serum in Chinese Holstein

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2211
Author(s):  
Shan Lin ◽  
Zihui Wan ◽  
Junnan Zhang ◽  
Lingna Xu ◽  
Bo Han ◽  
...  
Keyword(s):  
Association Studies ◽  
Significant Snps ◽  
Albumin Concentration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Chinese Holstein ◽  
Genome Wide ◽  
Chinese Holstein Cows ◽  
Newborn Calves

Albumin can be of particular benefit in fighting infections for newborn calves due to its anti-inflammatory and anti-oxidative stress properties. To identify the candidate genes related to the concentration of albumin in colostrum and serum, we collected the colostrum and blood samples from 572 Chinese Holstein cows within 24 h after calving and measured the concentration of albumin in the colostrum and serum using the ELISA methods. The cows were genotyped with GeneSeek 150 K chips (containing 140,668 single nucleotide polymorphisms; SNPs). After quality control, we performed GWASs via GCTA software with 91,620 SNPs and 563 cows. Consequently, 9 and 7 genome-wide significant SNPs (false discovery rate (FDR) at 1%) were identified. Correspondingly, 42 and 206 functional genes that contained or were approximate to (±1 Mbp) the significant SNPs were acquired. Integrating the biological process of these genes and the reported QTLs for immune and inflammation traits in cattle, 3 and 12 genes were identified as candidates for the concentration of colostrum and serum albumin, respectively; these are RUNX1, CBR1, OTULIN,CDK6, SHARPIN, CYC1, EXOSC4, PARP10, NRBP2, GFUS, PYCR3, EEF1D, GSDMD, PYCR2 and CXCL12. Our findings provide important information for revealing the genetic mechanism behind albumin concentration and for molecular breeding of disease-resistance traits in dairy cattle.

scholarly journals Animal-ImputeDB: a comprehensive database with multiple animal reference panels for genotype imputation

2019 ◽  
Vol 48 (D1) ◽  
pp. D659-D667 ◽  
Author(s):  
Wenqian Yang ◽  
Yanbo Yang ◽  
Cecheng Zhao ◽  
Kun Yang ◽  
Dongyang Wang ◽  
...  
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
High Quality ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Whole Genome Resequencing ◽  
Missing Genotypes

Abstract Animal-ImputeDB (http://gong_lab.hzau.edu.cn/Animal_ImputeDB/) is a public database with genomic reference panels of 13 animal species for online genotype imputation, genetic variant search, and free download. Genotype imputation is a process of estimating missing genotypes in terms of the haplotypes and genotypes in a reference panel. It can effectively increase the density of single nucleotide polymorphisms (SNPs) and thus can be widely used in large-scale genome-wide association studies (GWASs) using relatively inexpensive and low-density SNP arrays. However, most animals except humans lack high-quality reference panels, which greatly limits the application of genotype imputation in animals. To overcome this limitation, we developed Animal-ImputeDB, which is dedicated to collecting genotype data and whole-genome resequencing data of nonhuman animals from various studies and databases. A computational pipeline was developed to process different types of raw data to construct reference panels. Finally, 13 high-quality reference panels including ∼400 million SNPs from 2265 samples were constructed. In Animal-ImputeDB, an easy-to-use online tool consisting of two popular imputation tools was designed for the purpose of genotype imputation. Collectively, Animal-ImputeDB serves as an important resource for animal genotype imputation and will greatly facilitate research on animal genomic selection and genetic improvement.

scholarly journals Regulatory Variants and Disease: The E-Cadherin −160C/A SNP as an Example

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Gongcheng Li ◽  
Tiejun Pan ◽  
Dan Guo ◽  
Long-Cheng Li
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Regulate Gene Expression ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Regulatory Snps ◽  
E Cadherin

Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter −160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs.

scholarly journals Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18

2020 ◽  
Author(s):  
Huan Liu ◽  
Kaylia Duncan ◽  
Annika Helverson ◽  
Priyanka Kumari ◽  
Camille Mumm ◽  
...  
Keyword(s):  
Association Studies ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Support Vector ◽  
Oral Epithelium ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Regulatory Variant

AbstractGenome wide association studies for non-syndromic orofacial cleft (OFC) have identified single nucleotide polymorphisms (SNPs) at loci where the presumed risk-relevant gene is expressed in oral periderm. The functional subsets of such SNPs are difficult to predict because the sequence underpinnings of periderm enhancers are unknown. We applied ATAC-seq to models of human palate periderm, including zebrafish periderm, mouse embryonic palate epithelia, and a human oral epithelium cell line, and to complementary mesenchymal cell types. We identified sets of enhancers specific to the epithelial cells and trained gapped-kmer support-vector-machine classifiers on these sets. We used the classifiers to predict the effect of 14 OFC-associated SNPs at 12q13 near KRT18. All the classifiers picked the same SNP as having the strongest effect, but the significance was highest with the classifier trained on zebrafish periderm. Reporter and deletion analyses support this SNP as lying within a periderm enhancer regulating KRT18/KRT8 expression.

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